The purpose of the proposed research is to continue the molecular characterization of the feline immunodeficiency virus (FIV) genome. The overall goal of the study is to understand the role of each viral protein in the virus life cycle and to develop the feline/FIV model as a vehicle for design of treatments against lentivirus infections. The Specific Aims of the proposal are to 1) characterize the molecular interactions involved in receptor binding by FIV, both the binding to the chemokine receptor, CxCR4 as well as the identification and characterization of a putative second receptor. These studies will also include the characterization and mapping of monoclonal antibodies that we have generated that block CxCR4 binding to the surface glycoprotein and those that facilitate neutralization of the virus; 2) continue the characterization of the transactivator protein, Orf2, with emphasis on identification of interaction partners and definition of residues critical to Orf 2 function ; and 3) continue the molecular analysis of FIV Vif, including mutagenesis studies to define residues critical to Vif function. We will also attempt to identify Vif interaction partners and search for permissive cat cells that allow production of competent FIV in the absence of functional FIV, similar to cells identified as permissive and non-permissive for HIV Vif. The studies outlined will advance our knowledge of the FIV life cycle and further refine the model for use in the development of drug and vaccine-based intervention strategies.